Xamoterol improves the control of chronic atrial fibrillation in elderly patients

Age and Ageing, July, 1995 by P.J. Lawson-Matthew, K.A. McLean, M. Dent, C.A. Austin, K.S. Channer

Introduction

Atrial fibrillation is a common arrhythmia with a prevalence of 4% in people aged over 74 years [1]. It causes inefficient cardiac action because of the loss of atrio-ventricular synchrony and excessive exercise-induced tachycardia. Heart rate normally varies according to a diurnal rhythm under autonomic control; in atrial fibrillation the diurnal fluctuations in heart rate are greater. Drug treatment is aimed at normalizing heart rate by blocking atrio-ventricular conduction. Digoxin has traditionally been used in this context and reduces heart rate and improves effort tolerance. However, digoxin has a low therapeutic index and in doses sufficient to blunt exercise-induced tachycardia can cause nocturnal bradycardia with significant pauses (2). Other drugs also have effects on atrio-ventricular conduction and previous studies have shown that [beta]-adrenoceptor blocking agents when added to digoxin therapy improve heart-rate control during exercise [3, 4] but tend to exacerbate nocturnal bradycardia. [beta]-Adrenoceptor blockers with partial agovist activity both reduce diurnal tachycardia and nocturnal bradycardia and pauses [5, 6]. During the day sympathetic tone predominates causing an increase in resting heart rate on waking; exercise causes an immediate further increase in heart rate because of an abrupt reduction in parasympathetic tone and sympathetic activation, so [beta]-blockade reduces heart rate. At night parasympathetic tone is unopposed causing slowing of heart rate and pauses; [beta]-agonist activity reduces this. [beta]-Adrenoceptor blockers with partial agonist activity have been shown to be superior to selective [beta]-adrenoceptor blockers and calcium antagonists in reducing heart rate variability [5, 6]. Despite these therapeutic manipulations of heart rate and normalization of diurnal rate, [beta]-adrenoceptor blockers with and without partial agonist activity and calcium antagonists in combination with digoxin have not been shown to improve effort tolerance. Indeed, in some studies [7-8] effort tolerance has been decreased by [beta]-adrenoceptor blockers, possibly because of their intrinsic negative inotropic effects.

Xamoterol is a selective [B.sub.1]-adrenergic partial agonist. At low levels of sympathetic activity, it has been shown to produce positive inotropic and chronotropic effects on the heart [9]. With increased sympathetic activity, it acts as a competitive inhibitor at the [B.sub.1], receptor. Xamoterol when used alone and in combination with digoxin in patients with mild heart failure improves effort tolerance [10]. In patients with atrial fibrillation it also improves heart-rate control and in two small studies has been shown to improve effort tolerance [11-12]. This is the only drug other than digoxin to show a coincidence between improvement in heart-rate control and effort tolerance. Because atrial fibrillation is mainly an arrhythmia of elderly people, it is important to establish safety and efficacy of xamoterol in 'an elderly population. The aim of this study was to compare the effects of xamoterol alone and xamoterol plus digoxin on heart-rate control and symptoms in previously digitalized elderly patients.

Patients

Twenty-five patients initially entered the study. All patients had chronic atrial fibrillation and were attending hospital-based outpatient clinics. All had been treated for at least 3 months with digoxin, had an abbreviated mental state score [13] of >7/10 and were without contra-indications to [beta]-adrenoceptor blockers. Patients with mild heart failure (NYHA class I or II) were entered provided the requirement for loop diuretic was less than frusemide 80 mg or equivalent daily (13 patients were not taking loop diuretics). Mean daily dose of digoxin was 197 [mu]g (range 125-500[mu]g). At entry, all patients experienced some degree of breathlessness, palpitation or lethargy. Each patient gave informed consent and the study was approved by the local hospital Ethics Committee.

Methods

After baseline measurements, each patient received, in double-blind randomized order, treatment with xamoterol 200mg b.d. plus their usual dose of digoxin or xamoterol 200 mg b.d. plus placebo digoxin. At the end of 1 month of treatment, repeat assessments were made and treatment was crossed over. At the end of a further month of treatment, final assessments were made and the patients were asked to express a preference for one, either, or neither of the treatment choices.

Assessments at baseline and at the end of treatment periods included symptom scores, exercise tolerance and heart-rate control. Symptom scores of breathlessness, palpitation, and well-being were measured by visual analogue scales 100 mm in length and marked 0-100. Exercise tolerance was measured by 6-minute walking tests [14] along a flat marked corridor and 2-minute step-climbing test. During the test the patient was accompanied by a research worker and encouraged to walk at their usual pace. Rests were allowed but were counted within the time limits. End-points were distance walked in 6 minutes and total number of steps climbed in 2 minutes. Prior to randomization, patients were familiarized with the exercise tests.

Heart-rate control was measured by ambulatory 24-hour ECG recordings (Reynolds Tracker), and analysed by Reynolds Professional ECG analyser. Hourly minimum, mean and maximum heart rates were measured plus the frequency of ectopic beats and length of longest pauses. The total number of pauses >1.5 s was counted. Hourly counts with >300 s of artefact were excluded from the analysis.